Endometriosis-Associated Macrophages: Origin, Phenotype, and Function

Chloe Hogg, Andrew W. Horne, Horne AW, Erin Greaves, Greaves E
Frontiers in endocrinology · 2020 · vol. 11 , pp. 7 · doi:10.3389/fendo.2020.00007 · PMID:32038499 · PMC6989423 · W3001524003
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This review examines the origin, phenotype, and function of macrophages in endometriosis, highlighting their critical roles in lesion development and pain, and the potential for therapeutic targeting.

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This paper reviews what is known about macrophages in endometriosis, focusing on their possible origins (tissue-resident versus recruited monocyte-derived), phenotypic heterogeneity, and functions in lesion growth, vascularization, innervation, and pain generation. Drawing on evidence from immune-cell studies and broader macrophage biology, it argues that under disease-modified conditions macrophage homeostasis-like roles can shift to disease-promoting activities, while noting that direct evidence for macrophage origin and phenotypic diversity in endometriosis remains limited. It discusses etiologic theories (e.g., retrograde menstruation and potential roles for endometrial, neonatal, stem/progenitor, and metaplastic origins) and how these could plausibly alter macrophage recruitment and differentiation, but emphasizes gaps in proof for key proposed mechanisms. This paper is centrally about endometriosis — it reviews endometriosis-associated macrophage origin, phenotype, and function as they relate to lesion establishment and symptoms.

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Abstract

Endometriosis is a complex, heterogeneous, chronic inflammatory condition impacting ~176 million women worldwide. It is associated with chronic pelvic pain, infertility, and fatigue, and has a substantial impact on health-related quality of life. Endometriosis is defined by the growth of endometrial-like tissue outside the uterus, typically on the lining of the pelvic cavity and ovaries (known as "lesions"). Macrophages are complex cells at the center of this enigmatic condition; they are critical for the growth, development, vascularization, and innervation of lesions as well as generation of pain symptoms. In health, tissue-resident macrophages are seeded during early embryonic life are vital for development and homeostasis of tissues. In the adult, under inflammatory challenge, monocytes are recruited from the blood and differentiate into macrophages in tissues where they fulfill functions, such as fighting infection and repairing wounds. The interplay between tissue-resident and recruited macrophages is now at the forefront of macrophage research due to their differential roles in inflammatory disorders. In some cancers, tumor-associated macrophages (TAMs) are comprised of tissue-resident macrophages and recruited inflammatory monocytes that differentiate into macrophages within the tumor. These macrophages of different origins play differential roles in disease progression. Herein, we review the complexities of macrophage dynamics in health and disease and explore the paradigm that under disease-modified conditions, macrophages that normally maintain homeostasis become modified such that they promote disease. We also interrogate the evidence to support the existence of multiple phenotypic populations and origins of macrophages in endometriosis and how this could be exploited for therapy.
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The

Macrophages offer an attractive therapeutic target due to their instrumental role in a number of pathologies ( 79 ). Inhibition of macrophage signaling or recruitment, as well as re-education of disease-associated macrophages to a “healthy” phenotype could be of clinical benefit to patients where macrophages are implicated in disease pathophysiology. Identification of disease promoting macrophage populations and a detailed understanding of their regulation, recruitment and phenotype is a fundamental step before the development of therapeutics which specifically target disease-associated macrophages is possible. Due to the pivotal role that macrophages play in many cancers, macrophage-targeted therapies have received much attention in the literature and a number of in vivo studies and clinical trials have demonstrated efficacy in using macrophage-mediated treatments to improve clinical outcomes ( 79 ). A subset of studies has targeted proliferation of TAMs in an effort to alleviate tumor burden and improve clinical outcomes. Strachan et al. demonstrated that targeting the Csf-1-receptor with a small molecule inhibitor attenuated the turnover rate of TAMs and decreased tumor growth in mouse models of breast and cervical cancer ( 151 ). A phase I trial demonstrated a significant reduction in macrophage number in solid tumors after anti-Csf-1r treatment ( 152 ), and Csf-1r inhibition showed an improvement in clinical outcomes including improvement of symptoms in patients with diffuse-type giant cell tumors ( 153 ). Inhibiting macrophage proliferation therefore appears to be of clinical benefit in cancer models and subsets of cancer patients. Future treatments should aim to specifically target disease-associated macrophage populations; Csf-1 is a key regulator of macrophage proliferation and survival in most tissues and neutralization or inhibition would affect healthy macrophage populations and as such is not an ideal therapy ( 154 ). The proliferative capacity of endometriosis lesion-resident macrophages is currently unknown, thus further research is required to determine whether this treatment strategy would be of benefit to women with endometriosis. Another potential mechanism of therapeutic intervention could involve blocking recruitment of disease-promoting macrophage populations. The CCL2/CCR2 recruitment mechanism is implicated in a number of cancers and a CCR2 inhibitor to be administered alongside chemotherapy is currently in phase 1b trials ( 155 ). Inhibition of recruitment may be beneficial in blocking infiltration of macrophages into endometriosis lesions, however the mechanisms, which regulate recruitment into lesions, are currently poorly understood. Whilst progression of research into macrophage-targeted therapies is promising, current therapies do not specifically target disease-promoting macrophages but have the potential to affect macrophage populations throughout the whole body. However, as our understanding of disease-modified macrophages improves, it is evident that establishing macrophage origins and phenotype heterogeneity in disease are crucial areas of research before specific, targeted treatments can be designed ( 72 ). Future work describing macrophage sub-populations, active recruitment mechanisms and macrophage phenotype in endometriosis is therefore critically required before macrophage-targeted treatments may be a possibility for women with endometriosis.

Author

CH performed literature search and wrote manuscript. AH provided feedback. EG conceptualized manuscript, provided feedback, and wrote manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Etiology

It is widely accepted that endometriosis is a multifactorial disease and the pathophysiology of endometriosis can certainly be associated with a number of elements that clearly contribute to disease. Evidence suggests that endometriosis has a heritable component due to high familial incidence of the disease ( 19 – 22 ). A meta-analysis of eight genome-wide association studies (GWAS) elucidated six loci associated with endometriosis ( 23 ). Genes implicated in disease included those involved in the regulation of epithelial cells and hormone metabolism, specifically genes involved in regulating hormone responses in tissues ( 24 , 25 ). These GWAS results are not surprising since the symptoms of endometriosis are modulated by ovarian sex steroids; early age at menarche is a risk factor for development of endometriosis, suggesting increased exposure to estrogen may incur increased risk of disease ( 26 ). Endometriosis lesions aberrantly express a number of steroidogenic enzymes including aromatase and 17β-hydroxysteriod dehydrogenase (17β-HSD), this results in increased synthesis and decreased metabolism of estrogen ( 27 – 29 ) such that local levels remain high. Estrogen signaling modulates a large number of down-stream disease processes within endometriosis lesions, which are reviewed in Yilmaz and Bulun ( 30 ), Liang et al. ( 31 ), and Rizner ( 32 ). Immune cell dysfunction is also intrinsically linked to the pathophysiology of endometriosis. Alterations in immune cell populations have been observed in the peritoneal fluid of women with endometriosis; specifically, women with endometriosis have more peritoneal macrophages ( 33 ), neutrophils and dendritic cells ( 34 ). Function is also perturbed: NK cells have reduced cytotoxicity ( 35 , 36 ), and disease severity is positively correlated with NK cell killing capacity ( 37 ). Peritoneal macrophages also exhibit impaired phagocytosis ( 38 ). Macrophages are the most abundant immune cells present within endometriosis lesions and are evidently central to the pathophysiology of endometriosis. Whilst studies have highlighted clear functional roles for macrophages in the disorder, little is known regarding the origins and phenotypic heterogeneity of macrophages in endometriosis. Our understanding of endometriosis etiology remains limited. It is being increasingly recognized that different sub-types of endometriosis may arise from different origins, however evidence for this is still limited ( 39 , 40 ). A number of theories are discussed below and we speculate on how the origin and role of macrophages may differ in each scenario: The most widely accepted theory was postulated in 1927 by John Sampson, who observed that during menstruation, endometrial tissue can reflux back up the fallopian tubes and into the pelvic cavity, a physiological process known as “ retrograde menstruation .” Although this process occurs in ~90% of women, only in some does refluxed endometrial tissue form endometriosis lesions ( 41 ) and the mechanisms underpinning the attachment of endometrial tissue and lesion development remain elusive. It could be predicted, and mouse studies have demonstrated that macrophages originating from the endometrium contribute to peritoneal endometriosis lesions ( 42 ). These endometrial macrophages could be pivotal in the establishment of lesions since it has previously been demonstrated that macrophages trafficking to the endometrium are most abundant during repair following endometrial breakdown and shedding with a presumed role in repairing the denuded functional layer of the endometrium ( 43 ). However, evidence supporting this hypothesis is still absent. Another theory based on the dissemination of cells from the uterus into the peritoneal cavity suggests that neonatal retrograde reflux of endometrial stem/progenitor cells could be responsible for development of lesions. Visible vaginal bleeding is observed in 3–5% of female neonates, whereas occult bleeding may occur at a frequency of between 25 and 60% ( 44 ). Bleeding in the immediate postnatal period is similar to menstrual bleeding as it occurs in response to hormone withdrawal from in utero progesterone exposure. This theory suggests that stem/progenitor cells could implant into the peritoneal wall where they may remain dormant until adolescence, when elevated estrogen levels may then promote the proliferation and growth of seeded endometrial cells. Whilst, this theory represents a plausible mechanism of lesion formation, current evidence is lacking and proof that endometrial stem/progenitor cells are present in the peritoneal tissue of pre-pubescent girls is absent. The coelomic metaplasia theory suggests that endometriosis lesions arise as the result of metaplastic differentiation of the coelomic epithelium into endometrial cells and is supported by evidence suggesting endometriosis lesions can be found in women without a uterus ( 45 ). The formation of endometriosis lesions at sites distant from the peritoneal cavity ( 46 , 47 ), as well as identification in men on rare occasions ( 48 ) supports the theory. Upon development of lesions at the onset on adolescence (neonatal stem cell theory) or following metaplasia it would be expected that monocytes are recruited to the site of the lesion and/or that peritoneal macrophages may traffic into the developing lesion and activate repair processes that facilitate establishment of new endometrial-like explants. Notably, stem cells and macrophages are known to have a reciprocal relationship whereby stem cells can contribute to macrophage activation and phenotype during regenerative processes and macrophages can dictate accumulation of progenitor/stem cell-like cells ( 49 ). In endometriosis, mesenchymal stem-like cells promote macrophages to adopt a pro-repair phenotype ( 50 ) but further studies regarding the relationship between stem cells and macrophages in endometriosis are currently limited. Müllerianosis (müllerian rests; normal endometrial, endosalpingeal, and endocervical tissue) predicts that developmentally displaced tissue are incorporated into normal organs during organogenesis ( 51 ). Occurrence of deep infiltrating endometriosis particularly lends itself to this theory, where endometrial tissue is found deep within the organ structure. Speculation may infer a role for tissue-resident macrophages in lesions resulting from developmentally displaced endometrial-like tissue. Upon activation of a “dormant” lesion laid down during organogenesis the tissue-resident macrophages may change phenotype and proliferate such that they promote inflammation, growth, and invasion of the lesion. Inflammation arising upon activation of a dormant lesion may also lead to the recruitment of monocytes that differentiate into macrophages such that endometriosis lesion-resident macrophages are constituted by tissue-resident and monocyte-derived macrophages similar to what occurs in tumors ( 52 ). Any differences existing in macrophage origin, phenotype and function across the different subtypes of endometriosis lesions remain unknown.

Background

Endometriosis is defined by the presence of endometrial-like tissue outside the uterus (“lesions”), typically on the lining of the pelvic cavity (peritoneum) or on the ovaries. Endometriosis is a heterogeneous disease, and lesions can be categorized into three sub-types: superficial peritoneal, deep (infiltrating), and ovarian (“endometriomas”), where more than one sub-type can exist in the same patient and superficial peritoneal endometriosis is the most common form of disease ( 1 , 2 ). It is associated with debilitating chronic pelvic pain, infertility, and fatigue. It is estimated to affect 6–10% of women of reproductive age ( 3 ), up to 50% of infertile women ( 4 ) and is prevalent in 71–97% of women with chronic pelvic pain ( 5 ). Endometriosis-associated symptoms can negatively impact mental, physical and social well-being and quality of life ( 6 ). Poor pregnancy outcomes are also associated with the disease, including preterm labor, pre-eclampsia, ectopic pregnancy, miscarriage, and intrauterine growth restriction ( 7 ). Endometriosis has a significant socioeconomic impact, costing the UK an estimated £8.5 billion pounds each year, with societal cost being mostly attributed to loss of productivity ( 8 , 9 ). Diagnosis from onset of symptoms can take an average of 7–8 years. Generally, a diagnosis of endometriosis is achieved by laparoscopic evaluation of the pelvis, however imaging techniques such as transvaginal sonography and magnetic resonance imaging may be utilized to diagnose deep lesions and endometriomas ( 10 – 12 ). Endometriosis lesions are characterized by the presence of ectopic endometrial-like tissue containing glands and stroma, however recent re-evaluation of disease definition suggests that fibrosis and smooth muscle cells are more consistent features of lesions ( 13 ). Endometriosis is classified as an estrogen-dependent chronic inflammatory condition : symptoms are modulated by ovarian hormones and lesions generate intense inflammation within the pelvic cavity. Lesions also become vascularized and are infiltrated by sensory nerve fibers ( Figure 1 ). The ectopic endometrial cells and local inflammatory environment activate nerve fibers in lesions, establishing a dialogue with the central nervous system and generating pain in the condition. Lesions behave like the eutopic endometrium and exhibit cyclical bleeding into the pelvic cavity in response to ovarian hormones, and this acts to potentiate inflammation ( 14 ). Disease classification (rAFS/rASRM) is currently based on lesion size, location, extent of lesion infiltration into tissue and the presence of adhesions. Classification ranges from stage I (“minimal”) to stage IV (“severe”) ( 15 ). Endometriosis is a chronic inflammatory condition. Endometriosis is characterized by the presence of endometrial-like tissue found outside the uterus, most commonly in the peritoneal cavity. Endometriosis lesions are heterogenous but usually contain endometrial stromal cells and epithelial glands, immune cell infiltrates and are vascularized and innervated by nerves. Created using Biorender.com . Current treatments for endometriosis aim to alleviate endometriosis-associated pain and/or to treat infertility associated with the disease and include surgical and medical management ( 2 , 3 ). Ovarian suppression limits activity and growth of lesions, leading to reduced pain symptoms. Common methods of ovarian suppression include oral contraceptives and gonadotrophin-releasing hormone (GnRH) agonists ( 16 ) with add-back HRT. Whilst ovarian suppression may alleviate pain symptoms, treatment is also contraceptive and therefore inappropriate for women aiming to conceive. Additionally, GnRH agonists are associated with side effects such as memory loss, insomnia, and hot flushes in a recent study of endometriosis patients with long term use ( 17 ). Treatments can also include non-steroidal anti-inflammatory drugs such as ibuprofen, however long-term pain management for women with endometriosis often encompasses a combination of treatments. As well as medical therapy, laparoscopic surgery to remove lesions can provide symptom relief in some patients, however up to 50% of women experience a relapse of symptoms within 2 years after surgery ( 11 ). Current treatment options lack significant clinically proven benefit and aim at alleviating symptoms, rather than treating disease ( 18 ). Consequently, there is a compelling clinical need for new non-hormonal treatments that have fewer side effects and effectively treat endometriosis over a life course, without the need for repeated surgeries or suppression of fertility.

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Condition tags

endometriosischronic_pelvic_paininfertility

MeSH descriptors

Endometriosis Macrophages Macrophages Endometriosis Endometriosis Endometriosis Female Humans Macrophages Pelvic Pain Pelvic Pain Pelvic Pain Pelvic Pain Peritoneal Diseases Peritoneal Diseases Peritoneal Diseases Phenotype

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